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. 2013 Jan 2;31(2):313-8.
doi: 10.1016/j.vaccine.2012.11.008. Epub 2012 Nov 12.

Acinetobacter baumannii rOmpA vaccine dose alters immune polarization and immunodominant epitopes

Lin Lin  1 , Brandon Tan, Paul Pantapalangkoor, Tiffany Ho, Andrea M Hujer, Magdalena A Taracila, Robert A Bonomo, Brad Spellberg
Affiliations

Acinetobacter baumannii rOmpA vaccine dose alters immune polarization and immunodominant epitopes

Lin Lin et al. Vaccine. .

Abstract

Background: The rOmpA vaccine has been shown to protect mice from lethal infection caused by extreme-drug-resistant (XDR) Acinetobacter baumannii. The role of dose in immunology of the rOmpA vaccine was explored.

Methods: Mice were vaccinated with various doses of rOmpA plus aluminum hydroxide (Al(OH)(3)) adjuvant. The impact of dose on antibody titers, cytokine production, and immunodominant epitopes was defined.

Results: Anti-rOmpA IgG and IgG subtype titers were higher at larger vaccine doses (30 and 100 μg vs. 3 μg). The 3 μg dose induced a balanced IFN-γ-IL-4 immune response while the 100 μg dose induced a polarized IL-4/Type 2 response. Epitope mapping revealed distinct T cell epitopes that activated IFN-γ-, IL-4-, and IL-17-producing splenocytes. Vaccination with the 100 μg dose caused epitope spreading among IL-4-producing splenocytes, while it induced fewer reactive epitopes among IFN-γ-producing splenocytes.

Conclusions: Vaccine dose escalation resulted in an enhanced Type 2 immune response, accompanied by substantial IL-4-inducing T cell epitope spreading and restricted IFN-γ-inducing epitopes. These results inform continued development of the rOmpA vaccine against A. baumannii, and also are of general importance in that they indicate that immune polarization and epitope selectivity can be modulated by altering vaccine dose.

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Conflict of interest statement

Conflicts of Interest

LL and BS have filed a patent for the rOmpA vaccine.

Figures

Figure 1
Figure 1. Antibody titers induced by various doses of rOmpA or adjuvant alone
A) Balb/c mice (n = 11 per group from 3 separate experiments) were vaccinated with one of 3 doses of vaccine or adjuvant alone. IgG titers from individual mice and the median titers (horizontal bars) for each group are shown. B) IgM and IgG subtype titers measured by ELISA from vaccinated or control mice. *p < 0.05 vs. adjuvant alone; **p < 0.05 vs. adjuvant alone and vs. 3 µg dose.
Figure 2
Figure 2. Splenocyte cytokine production stimulated by rOmpA
A) IFN-γ, IL-4, or IL-17A production by splenocytes from vaccinated or control mice (n = 8 per group from 2 experiments) stimulated for 48 h with rOmpA measured by ELISpot. B) Ratio of IFN-γ:IL-4 produced by splenocytes from individual mice. Median and interquartile ranges are shown. *p < 0.05 vs. adjuvant control. **p < 0.05 vs. 3 and 30 µg dose, and vs. adjuvant control.
Figure 3
Figure 3. Vaccine dose altered epitope immunodominance
Splenocytes were harvested from Balb/c mice vaccinated with 3 or 100 µg of rOmpA. The splenocytes were stimulated with 5 µg/ml of individual, overlapping 15mer peptides for 48 hours in ELISpot plates. Graphed are the means of 2 mice per group each run in triplicate. The lower bound of the Y axis is set at the third quartile of responses across all peptides in order to focus on immunodominant epitopes.
Figure 4
Figure 4. B cell epitopes recognized by immune serum from vaccinated mice
A) SPOT synthesis membrane containing overlapping 13-mer peptides spanning the rOmpA sequence, offset by three amino acids, were probed with pooled immune serum from mice vaccinated with 3 µg of rOmpA. B) In silica homology model of rOmpA was built using the Swiss-Model automated protein structure homology-modeling server (http://swissmodel.expasy.org). Major immunogenic epitopes are color-coded. Red = spots 86–92 from Figure 4, dark blue = spots 102–105 from Figure 4; yellow = spots 107–108 from Figure 4; green (bottom right) = spots 40–41 from Figure 4.
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